Israel state records י"ב באדר התשס"ו March 12, 2006

R₂, R₃ and R₄ represent, independently, an H, hydroxyl, lower alkoxy, arylalkoxy, halo, lower haloalkyl, lower alkyl, lower alkenyl, cyano, lower cyanoalkyl, nitro, lower nitroalkyl, amido, lower amidoalkyl, (CH₂)_mNR₆R₇, (CH₂)_mC(O)R₈ (CH₂)_mSR₆, (CH₂)_mCO₂R₆, (CH₂)_mNR₆C(O)R₈, (CH₂)_mC(O)R₈, (CH₂)_mOC(O)R₈, O(CH₂)_mNR₆R₇, OC(O)NR₆R₇, OC(O)(CH₂)_mCO₂R₆, aryl or lower alrylalkyl radical substituted (i.e., substituted one to four times on the aryl group) or non-substituted, in which the substituent is lower alkyl, halo, nitro, amino, lower alkylamino, lower haloalkyl, lower hydroxyalkyl, lower alkoxy, or lower alkoxyalkyl) or R₂ and R₃, or R₃ and R₄, or R₄ and R₅, independently form together a chain with 3 or 4 links, in which the elements of the chain are selected from the group constituted by CH, CH₂, O, S, N or NR₉;

R₅ represents an H, halo, lower haloalkyl, lower alkyl, lower alkoxy, lower alkoxyalkyl, lower alkylthioalkyl, cycloalkyl, lower cycloalkylalkyl, cyano, cyanoalkyl, lower alkanesulphonylalkyl, lower hydroxyalkyl, nitro, (CH₂)_mC(O)R₈,

(CH₂)_mNR₆C(O)R₈, (CH₂)_mNR₆R₇, (CH₂)_mN(CH₃)(CH₂)_nNR₆R₇, (CH₂)_mOC(O)R₈, (CH₂)_mOC(O)NR₆R₇, aryl or lower arylalkyl radical substituted (i.e. one to four times on the aryl group) or non-substituted, in which the substituent is a lower alkyl, halo, nitro, amino, lower alkylamino, lower alkylalkyl, lower hydroxyalkyl, lower alkoxy or lower alkoxyalkyl;

R₆ and R₇ represent, independently, H, a lower alkyl, lower hydroxyalkyl, lower alkylaminoalkyl, lower aminoalkyl, cycloalkyl, lower cycloalkyl, lower alkenyl, lower alkoxyalkyl, lower haloalkyl, or aryl or lower arylalkyl radical substituted (i.e., one to four times on the aryl group) or non-substituted, in which the substituent is a lower alkyl, halo, nitro, amino, lower alkylamino, lower haloalkyl, lower hydroxyalkyl, lower alkoxy, or lower alkoxyalkyl, or else, when the chains R₆ and R₇ are attached to the same nitrogen atom, R₆ and R₇ optionally together form an aromatic or non-aromatic heterocycle, for example a heterocycle of morpholine, piperazine or piperidine type, said heterocycle being optionally substituted by one or more groups chosen from the lower alkyl, substituted or non-substituted aryl, substituted or non-substituted arylalkyl, halo, nitro, amino, lower alkylamino, lower haloalkyl, lower hydroxyalkyl, lower alkoxy or lower

alkoxyalkyl radicals;

R₈ represents an H, lower alkyl, lower hydroxyalkyl, amino, lower alkylamino, lower alkylaminoalkyl, lower aminoalkyl, cycloalkyl, lower cycloalkylalkyl, lower alkenyl, lower alkoxy, lower alkoxyalkyl, lower haloalkyl, or aryl or lower arylalkyl radical substituted (i.e., one to four times on the aryl group) or non-substituted, in which the substituent is a lower alkyl, halo, nitro, amino, lower alkylamino, lower haloalkyl, lower hydroxyalkyl, lower alkoxy, or lower alkoxyalkyl radical;

R₉ represents an H, lower alkyl, lower haloalkyl, aryl or arylalkyl radical, the aryl or arylalkyl group optionally being able to be substituted on the aromatic ring by one or more groups chosen from the lower alkyl, halo, nitro, amino, lower alkylamino, lower haloalkyl, lower hydroxyalkyl, lower alkoxy, or lower alkoxyalkyl radicals;

R₁₀ represents a cyano, C(O)OR₁₁, 1H-1,2,3,4-tetrazol-5-yl or 1-alkyl-1,2,3,4-tetrazol-5-yl radicals;

R₁₁ represents an H, lower alkyl, lower haloalkyl, lower hydroxyalkyl, alkylcarbonyloxyalkyl, (CH₂)_PNR₆R₇, aryl, arylalkyl or aryl radicals, the aryl or arylalkyl group optionally being able to be substituted on the aromatic ring by one or more groups chosen from the lower alkyl, halo, nitro, amino, lower alkylamino, lower haloalkyl, lower hydroxyalkyl, lower alkoxy, or lower alkoxyalkyl radical;

m is an integer comprised between 0 and 6;

n is an integer comprised between 1 and 4;

p is an integer comprised between 2 and 6;

or a pharmaceutically acceptable salt of the latter. Also claimed as new are compounds of the formula

Compounds of the formula

where n is 1 or 2, R is hydrogen, an acyl having 2 to 10 carbon atoms, an alkyl having from 1 to 6 carbons, or a blocking group, and X is L-tryptophan or D-tryptophan or a derivative thereof, and wherein the α carbon marked with an asterisk in Formula 1 has a stereoconfiguration, when n is 2, that is different from the stereoconfiguration of X.

m is 0 to 2;

n is 1 to 4;

r is 0 to 6;

R₄ and R₅ are independently selected from hydrogen or a C_1-2 alkyl;

R₆ is hydrogen, methyl, hydroxyl, aryl, halo substituted aryl, aryloxy C_1-3 alkyl, halo substituted aryloxy C_1-3 alkyl, indanyl, indenyl, C_7-11 polycycloalkyl,

provided that:

(a) when R₆ is hydroxyl, then m is 2; or

(b) when R₆ is hydroxyl, then r is 2 to 6; or

(c) when R₆ is 2-tetrahydropyranyl, 2-tetrahydrothiopyranyl, 2-tetrahydrofuranyl, or 2-tetrahydrothienyl, then m is 1 or 2; or

(d) when R₆ is 2-tetrahydropyranyl, 2-tetrahydrothiopyranyl, 2-tetrahydrofuranyl, or 2-tetrahydrothienyl, then r is 1 to 6;

(e) when n is 1 and m is 0, then R₆ is other than H in (CR₄R₅)_nO(CR₄R₅)_mR₆;

X is YR₂, halogen, nitro, NR₄R₅, or formyl amine;

Y is O or S(O)_m';

m' is 0, 1, or 2;

X₂ is O or NR₈;

X₃ is hydrogen or X;

X₄ is

X₅ is H, R₉, OR₈, CN, C(O)R₈, C(O)NR₈R₈, or NR₈R₈;

R₂ is independently selected from the group consisting of –CH₃ and –CH₂CH₃ optionally substituted by 1 or more halogens;

s is 0 to 4;

R₃ is hydrogen, halogen, C_1-4 alkyl, CH₂NHC(O)C(O)NH₂, halo-substituted C_1-4 alkyl, -CH=CR_8'R₈; cyclopropyl optionally substituted by R₈; CN, OR₈ CH₂OR₈, NR₈R₁₀, CH₂NR₈R₁₀, C(Z')H, C(O)OR₈, C(O)NR₈R₁₀, or C≡CR_8';

Z' is O, NR₉, NOR₈, NCN, C(-CN)₂, CR₈CN, CR₈NO₂, CR₈C(O)OR₈, CR₈C(O)NR₈R₈, C(-CN)NO₂, C-(CN)C(O)OR₉, or C(-CN)C(O)NR₈R₈;

Z is C(Y')R₁₄, C(O)OR₁₄, C(Y')NR₁₀R₁₄, C(NR₁₀)NR₁₀R₁₄, CN, C(NOR₈)R₁₄, C(O)NR₈NR₈C(O)R₈, C(O)NR₈NR₈C(O)R₈, C(O)NR₈NR₁₀R₁₄, C(NOR₁₄)R₈, C(NR₈)NR₁₀R₁₄, C(NR₁₄)NR₈R₈ C(NCN)NR₁₀R₁₄, C(NCN)SR₉, (2-, 4- or 5-imidazolyl), (3-, 4- or 5-pyrazolyl), (4- or 5-triazolyl[1,2,3]), (3- or 5-traizolyl [1,2,4]), (5-tetrazolyl), (2-, 4- or 5-oxazolyl), (3-, 4- or 5-isoxazolyl), (3- or 5-oxadiazolyl [1,2,4]), (2-oxadiazolyl [1,3,4]), (2-thiadiazolyl [1,3,4]), (2-, 4-, or 5-thiazolyl), (2-, 4-, or 5-oxazolidinyl), (2-, 4-, or 5-thiazolidinyl), or (2-, 4-, or 5-imidazolidinyl); wherein all of the heterocyclic ring systems may be optionally substituted one or more times by R₁₄;

the dotted line in formula (a) represents a single or double bond;

Y' is O or S;

R₇ is –(CR₄R₅)_qR₁₂ or C_1-6 alkyl wherein the R₁₂ or C_1-6 alkyl group is optionally substituted one or more times by C_1-2 alkyl optionally substituted by one to three fluorines, -F, -Br, -Cl, NO₂, -NR₁₀R₁₁, -C(O)R₈, -C(O)OR₈, -OR₈, -CN, -C(O)NR₁₀R₁₁, -OC(O)NR₁₀R₁₁, -OC(O)R₈, -NR₁₀C(O)NR₁₀R₁₁, -NR₁₀C(O)R₁₁, -NR₁₀C(O)OR₉, -NR₁₀C(O)R₁₃, -C(NR₁₀)NR₁₀R₁₁, -C(NCN)NR₁₀R₁₁, -C(NCN)SR₉, -NR₁₀C(NCN)SR₉, -NR₁₀(NCN)NR₁₀R₁₁, -NR₁₀S(O)₂R₉, -S(O)_mR₉, -NR₁₀C(O)C(O)NR₁₀R₁₁, -NR₁₀C(O)C(O)R₁₀, thiazolyl, imidazolyl, oxazolyl, pyrazolyl, triazolyl, or tetrazolyl;

q is 0, 1, or 2;

R₁₂ is C₃-C₇-cyclaolkyl, (2-, 3- or 4-pyridyl), pyrimidyl, pyrazolyl, (1- or 2-imidazolyl), thiazolyl, triazolyl, pyrrolyl, piperazinyl, piperidinyl, morpholinyl, furanyl, (2- or 3-thienyl), (4- or 5-thiazolyl), quinolinyl, naphthyl, or phenyl;

R₈ is independently selected from hydrogen or R₉;

R_8' is R₈ or fluorine;

R₉ is C_1-4 alkyl optionally substituted by one to three fluorines;

R₁₀ is OR₈ or R₁₁;

R₁₁ is hydrogen, or C_1-4 alkyl optionally substituted by one to three fluorines; or when R₁₀ and R₁₁ are as NR₁₀R₁₁ they may together with the nitrogen form a 5 to 7 membered ring optionally containing at least one additional heteroatom selected from O,N, or S;

R₁₃ is oxazolidinyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl, tetrazolyl, imidazolyl, imidazolidinyl, thiazolidinyl, isoxazolyl, oxadiazolyl, or thiadiazolyl, and each of these heterocyclic rings is connected through a carbon atom and each may be unsubstituted or substituted by one or two C_-12 alkyl groups;

R₁₄ is hydrogen or R₇; or when R₁₀ and R₁₄ are as NR₁₀R₁₄ they may together with the nitrogen form a 5 to 7 membered ring optionally containing one or more additional heteroatoms selected from O, N, or S;

provided that:

f) when R₁₂ is N-pyrazolyl, N-imidazolyl, N-triazolyl, N-pyrrolyl, N-piperazinyl, N-piperidinyl, or N-moprholinyl, then q is not 1; or

g) when X₂R₂ is OCF₂H or OCF₃, X is F, OCF₂H or OCF₃, X₃ is H, s is zero, X₅ is H, Z is C(O)OR₁₄ and R₁₄ is C_1-7 unsubstituted alkyl, then R₃ is other than H; or the pharmaceutically acceptable salts thereof, in the preparation of a medicament for treating COPD.

__________

137196			[21][11]
קוטל נגיפים			ANTIVIRALS			[54]
	15.01.1999					[22]
	SE	[33]	16.01.1998	[32]	9800116-7	[31]
	SE		16.01.1998		9800113-4
Int. Cl.7 A61K 031/44, A61P 031/18, C07D 213/75, 401/12, 413/12						[51]
			MEDIVIR AB, SWEDEN			[71]
	WO/1999/036406					[87]
לוצאטו את לוצאטו, גן תעשיה, עומר , ת.ד. 5352, באר שבע			LUZZATTO & LUZZATTO, P.O.B. 5352 BEER-SHEVA 84965			[74]

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